The present invention relates to new piperidyl- or piperazinyl-substituted- 1,2,3,4-tetrahydronaphthalene derivatives as (R)- enantiomers, (S)-enantiomers or racemates in the form of free base or pharmaceutically acceptable salts thereof, a process for their preparation, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds in therapy.
An object of the invention is to provide compounds for therapeutic use, especially compounds having a selective effect at a subgroup of 5-hydroxy-tryptamine receptors, designated the h5-HT1B-receptor (previously called the 5-HT1Dxcex2-receptor) in mammals including man.
It is also an object of the invention to provide compounds with a therapeutic effect after oral administration.
Different classes of piperazinyl substituted benzanilide derivatives as 5-HT1D antagonists are disclosed in inter alia EP 533266, EP 533267, EP 533268, GB 2273930 and WO 95/11243.
WO 94/13659 discloses an extremely broad class of fused benzo compounds having a para substituted piperidyl or piperazinyl radical in the aromatic ring, said class of compounds are stated to bind to the 5-HT1A receptor.
WO 94/21619 discloses fully aromatic naphthalene ring system which may be substituted with a piperidyl or piperazinyl group, said compounds are also stated to be potent serotonin (5HT1) agonists and antagonists.
EP 402923 discloses 2-aminoalkyl or alkylenaromatic substituted 1,2,3,4-tetrahydronaphthalene derivatives having a further nitrogen substitution in the 5 position in the tetraline ring, said compounds act as dopamine agonists.
Various central nervous system disorders such as depression, anxiety, etc. appear to involve the disturbance of the neurotransmitters noradrenaline (NA) and 5-hydroxytryptamine(5-HT), the latter also known as serotonin. The drugs most frequently used in the treatment of depression are believed to act by improving the neurotransmnission of either or both of these physiological agonists. It appears that the enhancement of 5-HT neurotransmission primarily affects the depressed mood and anxiety, whereas the enhancement of noradrenaline neurotransmission affects the retardation symptoms occurring in depressed patients. The invention concerns compounds which have an effect on 5-HT neurotransmission.
Serotonin, or 5-HT, activity is thought to be involved in many different types of psychiatric disorders. For instance it is thought that an increase in 5-HT activity is associated with anxiety, while a decrease in 5-HT release has been associated with depression. Serotonin has in addition been implicated in such diverse conditions as eating disorders, gastrointestinal disorders, cardiovascular regulation and sexual behavior.
The 5-HT Receptors
The various effects of 5-HT may be related to the fact that serotonergic neurons stimulate the secretion of several hormones, e.g. cortisol, prolactin, Bendorphin, vasopressin and others. The secretion of each of these other hormones appears to be regulated on a specific basis by several different 5-HT (serotonin) receptor subtypes. With the aid of molecular biology techniques, to date these receptors have been classified as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 with the 5-HT1 receptor further divided into the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F subtypes. Each receptor subtype is involved in a different serotonin function and has different properties.
Regulation of the 5-HT transmission
The release of 5-HT at the nerve terminals is feedback-regulated by two different subtypes of 5-HT receptors. Inhibitory 5-HT1A autoreceptors are located on the cell bodies in the raphxc3xa9 nuclei which upon stimulation by 5-HT decrease the impulse propagation in the 5-HT neurons and thereby reducing the 5-HT release at the nerve terminals. Another subtype of inhibitory 5-HT receptors is located on the 5-HT nerve terminals, the h5-HT1B receptors (in rodents the r5-HT1B receptors) which regulate the synaptic concentration of 5-HT by controlling the amount of 5-HT that is released. An antagonist of these terminal autoreceptors thus increases the amount of 5-HT released by nerve impulses which has been shown in both in vitro and in vivo experiments.
The use of an antagonist of the terminal h5-HT1B autoreceptor will accordingly increase the synaptic 5-HT concentration and enhance the transmission in the 5-HT system. It would thus produce an antidepressant effect making it useful as a medication for depression.
Other localizations of h5-HT1B receptor subtype also exist. A large part of these postsynaptic receptors appear to be located on nerve terminals of other neuronal systems (so calledheteroreceptors). Since the h5-HT1B receptor mediates inhibitory responses an antagonist of this receptor subtype might also increase the release of other neurotransmitters than 5-HT.
Compounds having h5-HT1B activity may according to well known and recognised pharmacological tests be divided into full agonists, partial agonists and antagonists.
The object of the present invention is to provide compounds having a selective effect at the h5-HT1B receptor, preferably antagonistic properties, as well as having a good bioavailability. The effect on the other receptors chosen from, for example, the 5-HT1A, 5-HT2A, DI, D2A, D3, xcex11 and xcex12 receptor has been investigated. Accordingly, the present invention provides compounds of the formula I 
X is N or CH;
Y is NR2CH2, CH2xe2x80x94NR2, NR2xe2x80x94CO, COxe2x80x94NR2 or NR2SO2 wherein R2 is H or C1-C6 alkyl;
R1 is H, C1-C6 alkyl or C3-C6 cycloalkyl;
R3 is C1-C6 alkyl, C3-C6 cycloalkyl or (CH2)n-aryl, wherein aryl is phenyl or a heteroaromatic ring containing one or two heteroatoms selected from N, O and S and which may be mono- or di-substituted with R4 and/or R5;
wherein R4 is H, C1-C6 alkyl, C3-C6 cycloalkyl, halogen, CN, CF3, OH, C1-C6 alkoxy, NR6R7, OCF3, SO3CH3, SO3CF3, SO2NR6R7, phenyl, phenyl-C1-C6 alkyl, phenoxy, C1-C6 alkyl phenyl, an optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO2 wherein the substituent(s) is(are) selected from C1-C6 alkyl, C3-C6 cycloalkyl and phenyl-C1-C6 alkyl, an optionally substituted heteroaromatic ring containing one or two heteroatoms selected from N, O and S wherein the substituent(s) is(are) selected from C1-C6 alkyl, C3-C6 cycloalkyl and phenyl-C1-C6 alkyl, or COR8;
wherein R6 is H, C1-C6 alkyl or C3-C6 cycloalkyl;
R7 is H, C1-C6 alkyl or C3-C6 cycloalkyl; and
R8 is C1-C6 alkyl, C3-C6 cycloalkyl, CF3, NR6R7, phenyl, a heteroaromatic ring containing one or two heteroatoms selected from N, O and S or a heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO2;
wherein R5 is H, OH, CF3, OCF3, halogen, C1-C6 alkyl or C1-C6 alkoxy;
n is 0-4;
R9 is C1-C6 alkyl, C3-C6 cycloalkyl, OCF3, OCHF2, OCH2F, halogen, CN, CF3, OH, C1-C6 alkoxy, C1-C6 alkoxy- C1-C6 alkyl, NR6R7, SO3CH3, SO3CF3, SO2NR6R7, an unsubstituted or substituted heterocyclic or heteroaromatic ring containing one or two heteroatoms selected from N, O and S wherein the substituent(s) is(are) C1-C6 alkyl; or COR8; wherein R6, R7 and R8 are as defined above,
as (R)-enantiomers, (S)-enantiomers or a racemate in the form of a free base or a pharmaceutically acceptable salt or solvate thereof which possess a high selective effect at the h5-HT1B receptor and also shows sufficient bioavailability after oral administration.
In the present context C1-C6 alkyl may be straight or branched. C1-C6 alkyl may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl,i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl
In the present context C1-C6 alkoxy may be straight or branched. C1-C6 alkoxy may be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, t-pentyloxy, neo-pentyloxy, n-hexyloxy or i-hexyloxy.
In the present context C3-C6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In the present context halogen may be fluoro, chloro, bromo or iodo.
In the present context the heteroaromatic ring containing one or two heteroatoms selected from N, O and S preferably is a 5- or 6-membered heteroaromatic ring and may be furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl or thienyl. The heteroaromatic ring can be either substituted or unsubstituted.
In the present context the heterocyclic ring containing one or two heteroatoms selected from N, O, S, SO and SO2 may optionally contain a carbonyl function and is preferably a 5-, 6- or 7-membered heterocyclic ring and may be imnidazolidinyl, inidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiomorpholinyl, preferably piperidirt, 1-piperazinyl, morpholino, thiomorpholino and 4-piperidon- 1-yl.
A preferred embodiment of the invention relates to compounds of formula I wherein Y is NHCO or CONH i.e. amides. Of those compounds, the compounds wherein R9 is C1-C6 alkyl, C1-C6 alkoxy, OCHF2 or OCH2F and R3 is unsubstituted phenyl, or mono- or di-substituted phenyl, and especially ortho-, meta- or para- substituted phenyl, and particularly those wherein the substituent R4 is phenyl, phenyl-C1-C6 alkyl, cyclohexyl, piperidino, 1-piperazinyl, morpholino, CF3, 4-piperidon-1, n-butoxy or COR8 wherein R8 is phenyl, cyclohexyl, 4-piperidon-1-yl, 1-piperazinyl, morpholino, CF3, piperidino or NR6R7, are preferred.